This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T790M is a secondary mutation that renders the EGFR kinase bearing the primary oncogenic mutations (such as L858R and deletions in exon 19) resistant to the old generation drugs including Iressa and Tarceva. Based on our previously determined EGFR T790M crystal structure and focused small molecule library screening for covalent inhibition, we were successful in identifying a new scaffold that can effectively inhibit the T790M bearing mutant EGFR and does not inhibit the wild-type EGFR. This structural study aimed to solve the complex structures of T790M with these newly identified inhibitors to help in understanding the molecular basis for the excellent specificity of the new scaffold and to facilitate further improvement of the new drug.